Approach Considerations

Patients with early, normal intrauterine pregnancies often present with signs and symptoms similar to those encountered in patients with ectopic pregnancies and other gynecologic or gastrointestinal conditions. The availability of various biochemical, ultrasonographic, and surgical modalities can aid the healthcare provider today in establishing a definitive diagnosis and differentiating among various conditions.

In order to reduce the morbidity and mortality associated with ectopic pregnancy, a high index of suspicion is necessary to make a prompt and early diagnosis. As mentioned earlier, neither risk factors nor signs and symptoms of ectopic pregnancy are sensitive or specific enough to establish a definitive diagnosis. Hence, screen any female patient in her reproductive years who presents with abdominal pain, cramping, or vaginal bleeding for pregnancy.

Serum and urine assays for the beta subunit of human chorionic gonadotropin (bhCG) have been developed to detect a pregnancy before the first missed period. While some commercial urine test kits are able to detect bhCG in early gestation, they are associated with varying false-negative rates. In addition, the need for a quantitative value makes serum bhCG the criterion standard for biochemical testing.

Evidence-based guidelines have been established for the diagnostic and therapeutic management of ectopic pregnancy.
[55] The highest adherence is the inclusion of vaginal ultrasonography in the workup (98%), whereas the lowest adherence (21%) is performing salpingostomy when the other tube is abnormal.

Blood type, Rh type, and antibody screen should be done in all pregnant patients with bleeding to identify patients in need of RhoGAM and to ensure availability of blood products in case of excessive blood loss.

In women with normal baseline findings for liver function tests (LFTs), renal function tests (RFTs), and complete blood count (CBC) on day 1 of single- or double-dose methotrexate (MTX) treatment for sonographically confirmed ectopic pregnancies, it may not be necessary to repeat these studies, as there appears to be no significant difference between results on day 1 and day 7 for either MTX treatment protocol.
[56]

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Beta–Human Chorionic Gonadotropin Levels

Serum and urine assays for the beta subunit of human chorionic gonadotropin (β-HCG) have been developed to detect a pregnancy before the first missed period. Although some commercial urine test kits are able to detect β-HCG in early gestation, they are associated with varying false-negative rates. In addition, the need for a quantitative value makes serum β-HCG the criterion standard for biochemical testing.

Rate of increase

Serum β-HCG levels correlate with the size and gestational age in normal embryonic growth. In a normal pregnancy, the β-HCG level doubles every 48-72 hours until it reaches 10,000-20,000mIU/mL. In ectopic pregnancies, β-HCG levels usually increase less.

In early, healthy intrauterine pregnancies, serum levels of β-HCG double approximately every 2 days (1.4-2.1 d). Kadar et al established that the lower limit of the reference range to which serum β-HCG should increase during a 2-day period is 66%.
[2] For example, a pregnant patient with a serum β-HCG level of 100 mIU/mL should have a serum β-HCG level of at least 166 mIU/mL 2 days later.

According to Kadar et al’s study, an increase in β-HCG of less than 66% would be associated with an abnormal intrauterine pregnancy or an extrauterine pregnancy. However, remember that 15% of healthy intrauterine pregnancies do not increase by 66% and that 13% of all ectopic pregnancies have normally rising β-HCG levels of at least 66% in 2 days.

Shepherd et al demonstrated that 64% of very early ectopic pregnancies initially may have normal doubling serum β-HCG levels.
[57] Later, Barnhart et al more reported that the minimum rise in serum β-HCG for a potentially viable pregnancy in women who present with vaginal bleeding or pain is 53% per 2 days (up to 5000 IU/L).
[58] Hence, intervention when the serum β-HCG level rises less than 66% but more than 53% should be undertaken according to other clinical and biochemical criteria.

Furthermore, even though ectopic pregnancies have been established to have lower mean serum β-HCG levels than healthy pregnancies, no single serum β-HCG level is diagnostic of an ectopic pregnancy. In short, serial serum β-HCG levels are necessary to differentiate between normal and abnormal pregnancies and to monitor resolution of ectopic pregnancy once therapy has been initiated.

Discriminatory zone

The discriminatory zone of β-HCG is the level above which a normal intrauterine pregnancy is reliably visualized. Once β-HCG has reached a level of 700-1000 mIU/mL, a gestational sac should be seen within the uterus on transvaginal ultrasonographic images. Once it has reached 6000 mIU/mL, a gestational sac should be visualized within the uterus on abdominal scan images.

The lack of an intrauterine pregnancy when the β-HCG level is above the discriminatory zone represents an ectopic pregnancy or a recent abortion.

Drawbacks to β-HCG testing

The major disadvantage in relying on serial β-HCG titers to distinguish between normal and abnormal pregnancies is the potential for delay in reaching the diagnosis. Furthermore, although serial β-HCG titers may be used to differentiate between a normal and an abnormal gestation, the test does little to indicate the location of the pregnancy. Hence, additional diagnostic modalities, including ultrasonography and other biochemical markers, are needed.

Another disadvantage is in cases of multiple gestations; if a multiple gestation is suspected, as in pregnancies resulting from assisted reproduction, the β-HCG discriminatory zone must be used cautiously. Patients with normal multiple gestates were found to have levels of β-HCG above the discriminatory zone before any ultrasonographic evidence of the gestation was apparent,
[2] and they showed multiple gestations with β-HCG levels of up to 2300 mIU/mL before transvaginal ultrasonographic recognition.

Also remember that a discriminatory zone is operator and institution dependent; the clinician must be aware of the zone used by a particular institution before interpreting results there.

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Progesterone Levels

A single serum progesterone level is another tool that is useful in differentiating abnormal gestations from healthy intrauterine pregnancies. Serum progesterone levels have the following characteristics:

They are not gestational age–dependent

They remain relatively constant during the first trimester of normal and abnormal pregnancies

They do not return to the reference range if initially abnormal

They do not correlate with beta–human chorionic gonadotropin (β-HCG) levels

However, no consensus on a single progesterone value that differentiates between a normal and an abnormal pregnancy currently exists.

Several authors have proposed different cutoffs with varying sensitivity and specificity. In one large study, a progesterone value of greater than 25 ng/mL excluded ectopic pregnancy with 97.4% certainty. Furthermore, levels of 5 ng/mL or less indicated a nonviable pregnancy, ectopic or intrauterine, and excluded normal pregnancy with 100% sensitivity.

Although inexpensive, the usefulness of serum progesterone is limited by the fact that a significant number of results fall in the equivocal range of 5-25 ng/mL. Also, this test is unreliable in differentiating between normal and abnormal pregnancies in patients who conceive after in vitro fertilization (IVF), because of excessive progesterone production from multiple corpora lutea, as well as the practice of pharmacologic progesterone supplementation.

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Other Markers

Several other serum and urine markers are under investigation to help distinguish normal and abnormal pregnancies. These include serum estradiol, inhibin, pregnancy-associated plasma protein A, pregnanediol glucuronide, placental proteins, creatinine kinase, and a quadruple screen of serum progesterone, beta–human chorionic gonadotropin (β-HCG), estriol, and alfa-fetoprotein (AFP). These markers are usually either early pregnancy proteins or signs of inflammation and damage in smooth muscles and have not been sufficiently sensitive to be useful in clinical medicine.

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Ultrasonography

Ultrasonography is probably the most important tool for diagnosing an extrauterine pregnancy, although it is more frequently used to confirm an intrauterine pregnancy.

Visualization of an intrauterine sac, with or without fetal cardiac activity, is often adequate to exclude ectopic pregnancy.
[3] The exception to this is in cases of heterotopic pregnancies, which occur in between 1 in 4000 and 1 in 30,000 spontaneous pregnancies.

In patients undergoing ovarian stimulation and assisted reproduction, screening the adnexa by ultrasonography is mandatory even when an intrauterine pregnancy has been visualized, because these patients have a 10-fold increased risk of heterotopic pregnancy. Heterotopic pregnancy is a combined intrauterine and ectopic pregnancy, and it may occur in approximately 1 in 30,000.

The value of ultrasonography is highlighted further by its ability to demonstrate free fluid in the cul-de-sac. However, although free fluid can represent hemoperitoneum, it is not specific for ruptured ectopic pregnancy. Free fluid on ultrasonographic images can represent physiologic peritoneal fluid or blood from retrograde menstruation and unruptured ectopic pregnancies.

Ultrasonography can also be used to detect the presence of other pathologic conditions that may display the signs and symptoms of ectopic pregnancy. For example, although cesarean scar ectopic pregnancy (CSEP) is a rare occurrence, its frequency appears to be increasing with the increasing number of cesarean sections being performed.
[7] Early endovaginal ultrasonography may be used to detect CSEPs, thereby helping to minimize maternal complications, maintain treatment options, and potentially preserve future fertility.
[7]

Transvaginal/endovaginal ultrasonography

Transvaginal ultrasonography, or endovaginal ultrasonography, with its greater resolution, can be used to visualize an intrauterine pregnancy by 24 days post ovulation or 38 days after the last menstrual period (which is about 1 week earlier than transabdominal ultrasonography can be used for this). This imaging technique can be performed in the outpatient clinic or emergency department and has been reported to have a sensitivity of 90% and a specificity of 99.8%, with positive and negative predictive values of 93% and 99.8% respectively.
[59] About 75% of tubal pregnancies can be detected by transvaginal ultrasonography.
[60]

Gestational sac

The gestational sac, which is an ultrasonographic term and not an anatomic term, is the first structure that is recognizable on transvaginal ultrasonographic images. It has a thick, echogenic rim surrounding a sonolucent center corresponding to the trophoblastic decidual reaction surrounding the chorionic sac. Structures that represent a developing embryo cannot be recognized until a later time.

A pseudosac is a collection of fluid within the endometrial cavity created by bleeding from the decidualized endometrium and is often associated with an extrauterine pregnancy; this should not be mistaken for a normal, early intrauterine pregnancy. The true gestational sac is located eccentrically within the uterus beneath the endometrial surface, whereas the pseudosac fills the endometrial cavity.

The yolk sac is the first visible structure within the gestational sac. It resembles a distinct circular structure with a bright, echogenic rim and a sonolucent center. It can first be recognized at 3 weeks post conception, about 5 weeks after the last menstrual period. The embryo is recognized first as a thickening along the edge of the yolk sac; embryonic cardiac motion can be observed at 3.5-4 weeks post conception, about 5.5-6 weeks after the last menstrual period.

Definite intrauterine pregnancy

In a definite intrauterine pregnancy, a gestational sac with a sonolucent center (>5 mm in diameter) is surrounded by a thick, concentric, echogenic ring located within the endometrium and contains a fetal pole, a yolk sac, or both. (See the image below.)

In a probable abnormal intrauterine pregnancy, the gestational sac is larger than 10 mm in diameter, without a fetal pole or with a definite fetal pole but without cardiac activity. This frequently has an irregular or crenelated border.

Presumed ectopic pregnancy

An empty uterus on endovaginal ultrasonographic images in patients with a serum beta–human chorionic gonadotropin (β-HCG) level greater than the discriminatory cutoff value is an ectopic pregnancy until proven otherwise. An empty uterus may also represent a recent abortion.

Definite ectopic pregnancy

In the presence of a definite ectopic pregnancy, a thick, brightly echogenic, ringlike structure is located outside the uterus, with a gestational sac containing an obvious fetal pole, a yolk sac, or both. This is an unusual finding.

Other ultrasonographic findings in ectopic pregnancy

Findings such as an adnexal mass (usually a corpus luteum, occasionally hematoma), free cul-de-sac fluid, and/or severe adnexal tenderness with probe palpation may be present. Patients with no definite intrauterine pregnancy and the above-mentioned findings may be at high risk for an ectopic pregnancy.
[61, 62]

An appreciation for the spectrum of ultrasonographic findings in ectopic pregnancy, discussed below, may allow physicians to recognize an early ectopic pregnancy.

Tubal ring

A tubal ring is an echogenic, ringlike structure found outside of the uterus that represents an early ectopic pregnancy.

Extrauterine mass

The presence of a tender adnexal mass on ultrasonographic images suggests an ectopic pregnancy. One study suggested that the presence of any adnexal mass other than a simple cyst was the most significant ultrasonographic finding for the diagnosis of ectopic pregnancy.

Interstitial ectopic pregnancy

An interstitial ectopic pregnancy implants at the highly vascular region of the uterus near the insertion of the fallopian tube. These types can grow larger than those within the fallopian tube, because the endometrial tissue is more expandable. Owing to the increased size and partial endometrial implantation, these advanced ectopic pregnancies can be misdiagnosed as intrauterine pregnancies.

An aid in the diagnosis of an interstitial ectopic pregnancy is the eccentric location of the gestational sac. Evaluating the amount of uterine myometrium surrounding the gestational sac and echogenic decidual layer is important. This is termed the myometrial mantle. At least 5 mm of myometrium should be present. The presence of less than 5mm suggests the diagnosis. Another ultrasonographic finding is the interstitial line sign.

Hemosalpinx and ruptured ectopic pregnancy

A hemosalpinx is a condition in which the fallopian tubes may fill with blood or free fluid. Findings of a ruptured ectopic pregnancy on ultrasonographic images include free fluid or clotted blood in the cul-de-sac or in the intraperitoneal gutters, such as the Morrison pouch.

Ultrasonography and discriminatory zone of β-HCG

In the absence of reliable menstrual and ovulatory history, a discriminatory zone of β-HCG levels validates the ultrasonographic findings. The discriminatory zone is the level of β-HCG (using the Third International Standard for quantitative β-HCG) at which all intrauterine pregnancies should be visible on ultrasonography. With abdominal ultrasonography, that level is 6000-6500 mIU/mL, but high-resolution transvaginal ultrasonography has reduced this level to 1500-1800 mIU/mL. If transvaginal ultrasonography does not reveal an intrauterine pregnancy when the discriminatory β-HCG levels are reached, the pregnancy generally can be considered extrauterine.

An exception to this is multiple gestations. Kadar et al reported that patients with normal multiple gestates not only had levels of β-HCG above the discriminatory zone before any ultrasonographic evidence of the gestation was apparent, they also showed that multiple gestations with β-HCG levels of up to 2300 mIU/mL could be present before transvaginal ultrasonographic recognition.
[2] Therefore, if a multiple gestation is suspected, as in pregnancies resulting from assisted reproduction, the β-HCG discriminatory zone must be used cautiously.

Nonetheless, the effectiveness of using ultrasonography with a discriminatory zone of β-HCG levels has been well established in the literature.

In one large study of more than 1200 patients, Barnhart et al reported that 78.8% of patients were diagnosed definitively at the initial visit using an algorithm that included the use of ultrasonography, along with serum β-HCG levels above the discriminatory zone.
[63] In this study, if the patient's serum β-HCG level was above the established discriminatory zone at initial presentation and an intrauterine sac was not identified, an operative approach involving curettage and possible operative laparoscopy was used to diagnose ectopic pregnancy.
[63]

If the patient's serum β-HCG levels were below the discriminatory zone, serial β-HCG titers were performed every 2 days. Once a patient's levels reached the discriminatory zone, ultrasonography was performed.
[63] If, however, the patient's β-HCG levels failed to rise appropriately (ie, at least 66% in 2 d), operative intervention was undertaken with dilatation and curettage or with laparoscopy, to exclude the diagnosis of ectopic pregnancy. With this protocol, Barnhart et al reported a sensitivity of 100% and a specificity of 99.9%.
[63]

A discriminatory zone is operator and institution dependent, and the clinician must be aware of the zone used by a particular institution before interpreting results.

Doppler ultrasonography

Color-flow Doppler ultrasonography has been demonstrated to improve the diagnostic sensitivity and specificity of transvaginal ultrasonography, especially in cases in which a gestational sac is questionable or absent. A study of 304 patients at high risk for ectopic pregnancy found that the use of color-flow Doppler ultrasonography, compared with transvaginal ultrasonography alone, increased the diagnostic sensitivity from 71% to 87% for ectopic pregnancy, from 24% to 59% for failed intrauterine pregnancy, and from 90% to 99% for viable intrauterine pregnancy.

The addition of color-flow Doppler ultrasonography may expedite earlier diagnosis and eliminate delays caused by using levels of β-HCG for diagnosis. Furthermore, color-flow Doppler ultrasonography can potentially be used to identify involuting ectopic pregnancies that may be candidates for expectant management.

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Dilatation and Curettage

A simple way to rule out an ectopic pregnancy is to establish the presence of an intrauterine pregnancy. Once the presence of an abnormal pregnancy has been established by assessing beta–human chorionic gonadotropin (β-HCG) or progesterone levels, dilatation and curettage can provide a rapid, cost-effective method to help differentiate between an intrauterine and an ectopic pregnancy.

If the tissue obtained is positive for villi by floating in saline or by histologic diagnosis on frozen or permanent section, then a nonviable intrauterine pregnancy has occurred. In the absence of villi, the diagnosis of ectopic pregnancy is made. Laparoscopy can be performed at that time, or the case may be followed using serial serum β-HCG levels and be treated medically or surgically at a later time, depending on the clinical setting.

This method of diagnostic dilatation and curettage may be used, of course, only in cases in which continuation of a pregnancy is not desired even if it were an intrauterine gestation.

In a patient undergoing a dilatation and curettage for the diagnosis of ectopic pregnancy, obtaining consent for a diagnostic, and possibly operative, laparoscopy is also necessary in case the diagnosis of ectopic pregnancy is made; this spares the patient exposure to an additional operative procedure.

Although dilatation and curettage is easy and effective, it can provide false reassurance in cases of heterotropic pregnancies, in which multiple gestations are present, with at least 1 being intrauterine and 1 being extrauterine.

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Culdocentesis

Culdocentesis is another rapid and inexpensive method of evaluation for ruptured ectopic pregnancy. It is performed by inserting a needle through the posterior fornix of the vagina into the cul-de-sac and attempting to aspirate blood. When nonclotting blood is found in conjunction with a suspected ectopic pregnancy, operative intervention is indicated, because the likelihood of a ruptured ectopic pregnancy is high.

Although culdocentesis is of historic interest, its use today is rare. This procedure is associated with a high false-negative rate (10-14%), usually reflecting blood from an unruptured ectopic pregnancy, a ruptured corpus luteum, an incomplete abortion, or retrograde menstruation. Furthermore, the improved technology with ultrasonographic and hormonal assays is far superior in sensitivity and specificity in reaching the correct diagnosis.

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Laparoscopy

Patients in pain and/or those who are hemodynamically unstable should proceed to laparoscopy. Laparoscopy allows assessment of the pelvic structures, the size and exact location of the ectopic pregnancy, the presence of hemoperitoneum (see the image below), and the presence of other conditions, such as ovarian cysts and endometriosis, which, when present with an intrauterine pregnancy, can mimic an ectopic pregnancy. Furthermore, laparoscopy provides the option to treat once the diagnosis is established.

Laparoscopic picture of an unruptured right ampullary tubal pregnancy; bleeding out of the fimbriated end has resulted in hemoperitoneum.

Laparoscopy remains the criterion standard for diagnosis; however, its routine use on all patients suspected of ectopic pregnancy may lead to unnecessary risks, morbidity, and costs. Moreover, laparoscopy can miss up to 4% of early ectopic pregnancies; as more ectopic pregnancies are diagnosed earlier in gestation, the rate of false-negative results with laparoscopy would be expected to rise.

Laparoscopic picture of an unruptured right ampullary tubal pregnancy; bleeding out of the fimbriated end has resulted in hemoperitoneum.

A 12-week interstitial gestation, which eventually resulted in a hysterectomy. Courtesy of Deidra Gundy, MD, Department of Obstetrics and Gynecology at Medical College of Pennsylvania and Hahnemann University (MCPHU).

A 12-week interstitial gestation, which eventually resulted in a hysterectomy. Courtesy of Deidra Gundy, MD, Department of Obstetrics and Gynecology at Medical College of Pennsylvania and Hahnemann University (MCPHU).

Robert K Zurawin, MD Associate Professor, Director of Baylor College of Medicine Program for Minimally Invasive Gynecology, Director of Fellowship Program, Minimally Invasive Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine